The central hypothesis of this project is that synaptic plasticity in each of multiple hippocampal excitatory circuits contributes to the overall role of the hippocampus in learning and memory by providing distinct and complementary functions. While such ideas have been modeled extensively, empirical studies have been scant due to technical difficulties. The recently invented cell type-restricted gene knockout technique and multidisciplinary analyses of the resulting mutants provide an effective approach. Following our previous studies on CA1 and CA3 circuits, this project focuses on dentate gyrus (DG). We propose to generate an NMDA receptor (NR) knockout mouse strain in which the gene ablation is selective in adult DG granule cells. By subjecting the mutant mice to specifically designed behavioral protocols, we will test the hypothesis that the plasticity at the perforant path (PP)-DG synapses plays a crucial role in pattern separation and other specific aspects of hippocampus-dependent learning and memory. Applying the multielectrode recording technique to the mutant mice undergoing a specifically designed spatial memory task ( wagon wheel maze"), we will seek, in collaboration with Matthew Wilson, hippocampal neuronal activity correlates of the putative behavioral impairments. We also propose to generate GluR6 (G6) knockout mouse strains in which the gene ablation is selective either in DG granule cells or CA3 pyramidal cells. In collaboration with Steve Heinemann, we will determine whether pre- or post-synaptic G6 gates plasticity at the mossy fiber (MF)-CA3 synapses. By subjecting these mutants to several behavioral tasks, we will examine whether the MF synaptic plasticity plays a crucial role in specific aspects of memory, pattern separation, pattern completion and rapid one-trial learning. We will also seek hippocampal neuronal activity correlates of putative behavioral impairments. We will extend these studies to cell type-restricted, reversibly inducible NR1 and G6 mutant mice when they become available from the Center's Core #1 project. These multidisciplinary and collaborative studies will advance our fundamental knowledge about the roles of hippocampal circuits in learning and memory and, thereby, contribute to mental health and illness because mnemonic impairments are a hallmark of aging and major neurodegenerative diseases such as Alzheimer's and Parkinsons's disease.